There is a need to create new biotechnology to safely and effectively deliver miRNA to target cells of interest in the brain. We propose to develop enhanced polymeric nanoparticles designed to be stable extracellularly and bioreducible intracellularly, to enable safe and effective delivery of miRNA. We will validate these particles in models of brain cancer as it is a deadly disease that is in critical need of new therapies. In particular, we will evaluate treatment of human glioblastoma in orthotopic models compared to the standard of care. Polymer structures will be synthesized and utilized to fabricate non-viral nanoparticles for delivery to multiple brain cell types including healthy cells and cancer cells. Nanoparticle formulations will be developed that remain stable in cerebrospinal fluid (CSF) and that can spread throughout the brain following administration by convection-enhanced delivery (CED). We will investigate novel miRNA drugs capable of overcoming known drug and radiation resistances by targeting tumor-propagating brain cancer stem cells (BCSCs). Novel miRNA combinations will be evaluated in vitro and in vivo. The nanoparticles will be tracked to evaluate their intracellular and extracellular delivery and cell specificity. Transport and safety through normal and tumor- bearing rodent brains following CED will be analyzed. Leading nanoparticles will be evaluated in an orthotopic model for human glioblastoma using molecular and cell biological endpoints and anti-tumor efficacy will be compared to the standard of care as well as in combination with the standard of care. We will create an innovative technology for miRNA delivery and validate it in models of brain cancer.